A review of species differences in the control of, and response to, chemical-induced thyroid hormone perturbations leading to thyroid cancer

Foster, John R.; Tinwell, H.; Melching-Kollmuß, Stephanie

doi:10.1007/s00204-020-02961-6

Cited by 29 publications

(30 citation statements)

References 225 publications

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“…Although sensitivity to inducer-mediated thyroid disruption leading to increased TSH and tumorigenesis is established to be greater in rats versus mice, and even less relevant in humans due in part to the lack of thyroxine-binding globulin, shorter half-life of thyroid hormone, and higher TSH in rats, data exist indicating that selective inducers of PXR (rifampin) and CAR activators (carbamazepine, phenytoin) can reduce human blood levels of thyroid hormone (Noyes et al, 2019;Foster et al, 2021;Van Groen et al, 2021). This indicates there is responsiveness in humans to hepatic enzyme inducers of thyroid hormone disposition.…”

Section: Current Hypothesis Gaps and Future Considerationsmentioning

confidence: 99%

“…Comprehensive reviews of the various modes of action of chemicals on thyroid function and the contribution of this to human risk assessment, considering adverse outcome-based approaches and testing strategies, have been published recently (Murk et al, 2013;Noyes et al, 2019;Foster et al, 2021). This mini review focuses on data generated from experimental rat models that characterized the altered disposition of thyroid hormones in the presence of inducing chemicals to bring forward a current understanding of the likely pathway(s) by which these chemicals act, as depicted in Figure 1.…”

Section: Introductionmentioning

confidence: 99%

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Mechanisms by Which Inducers of Drug Metabolizing Enzymes Alter Thyroid Hormones in Rats

Vansell

2022

Drug Metab Dispos

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Increased disposition of thyroid hormones is a way that xenobiotics may alter thyroid homeostasis and in rats, produce thyroid follicular adenoma/carcinoma. This capacity is historically attributed to induction of T4 glucuronidation by UGT enzymes, and cytochrome P450 induction is often a surrogate. However, gaps exist in correlating the effectiveness of certain chemical inducers at increasing T4 glucuronidation with decreases in systemic T4 and resulting increases in TSH. With the identification of other key inducible drug processing genes and proteins involved in hepatic disposition of thyroid hormones, including uptake (eg, Oatps) and efflux (eg, Mrps) transporters, data exist that support transporters as additional targets sites of induction. These data are reviewed herein and indicate an increase in hepatic uptake of thyroid hormones, as well as increased biliary excretion of iodothyronine conjugates, represent critical activities that differentiate inducer effectiveness in disrupting thyroid hormones in rats. Increased membrane transport of thyroid hormones, likely in conjunction with induced glucuronidation of thyroid hormone (T3 more relevant than T4), provide a better indication of thyroid disrupting potential than consideration of UGT induction alone. Because coordinate regulation of these targets is inconsistent among inducers belonging to various classes and among species, and there are disparities between in vitro assays and in vivo responses, further work is required to identify specific and relevant inducible thyroid hormone uptake transporters. Data from Mrp2-null animals has contributed key information, yet the contributions of efflux transport (canalicular and basolateral) to the mechanism of individual, effective inducers also requires further study.

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Section: Current Hypothesis Gaps and Future Considerationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mechanisms by Which Inducers of Drug Metabolizing Enzymes Alter Thyroid Hormones in Rats

Vansell

2022

Drug Metab Dispos

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“…The liver, along with being a first-pass organ for the oral route of exposure, is also one of the most common tumor sites in bioassays of industrial chemicals and agrochemicals ( Heusinkveld et al , 2020 ; Hill et al , 2017 ). The extensive set of xenobiotic receptors in liver can serve as transcriptional sensors and sentinels of activity of a chemical that may or may not be tumorigenic in rat liver but would be predicted to be tumorigenic in distant tissues, such as the thyroid or gonads ( Foster et al , 2021 ; Klaunig et al , 2003 ; Murphy and Korach, 2006 ; Ohara et al , 2018 ; Sistare et al , 2011 ; Vansell and Klaassen, 2002 ). Liver transcriptomics can inform if a compound with direct or indirect (anti)estrogenic ( Singhal et al , 2009 ; Ståhlberg et al , 2005 ) or (anti)androgenic activity ( Goetz and Dix, 2009 ; Klaunig et al , 2003 ) may cause tumors in sex organs ( Coulson et al , 2003 ).…”

Section: Transcriptomic Biomarkers Predictive Of Tumorigenic Mechanis...mentioning

confidence: 99%

A Collaborative Initiative to Establish Genomic Biomarkers for Assessing Tumorigenic Potential to Reduce Reliance on Conventional Rodent Carcinogenicity Studies

Corton

Mitchell

Auerbach

et al. 2022

Toxicological Sciences

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There is growing recognition across broad sectors of the scientific community that use of genomic biomarkers has the potential to reduce the need for conventional rodent carcinogenicity studies of industrial chemicals, agrochemicals, and pharmaceuticals through a weight-of-evidence approach. These biomarkers fall into 2 major categories: (1) sets of gene transcripts that can identify distinct tumorigenic mechanisms of action; and (2) cancer driver gene mutations indicative of rapidly expanding growth-advantaged clonal cell populations. This call-to-action article describes a collaborative approach launched to develop and qualify biomarker gene expression panels that measure widely accepted molecular pathways linked to tumorigenesis and their activation levels to predict tumorigenic doses of chemicals from short-term exposures. Growing evidence suggests that application of such biomarker panels in short-term exposure rodent studies can identify both tumorigenic hazard and tumorigenic activation levels for chemical-induced carcinogenicity. In the future, this approach will be expanded to include methodologies examining mutations in key cancer driver gene mutation hotspots as biomarkers of both genotoxic and nongenotoxic chemical tumor risk. Analytical, technical, and biological validation studies of these complementary genomic tools are being undertaken by multisector and multidisciplinary collaborative teams within the Health and Environmental Sciences Institute. Success from these efforts will facilitate the transition from current heavy reliance on conventional 2-year rodent carcinogenicity studies to more rapid animal- and resource-sparing approaches for mechanism-based carcinogenicity evaluation supporting internal and regulatory decision-making.

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“…The thyroid gland is one of the main target organs of EDCs. In laboratory animals (mainly rodents), perturbation of the thyroid hormone (TH) homeostasis has been shown for several plant protection products (PPPs) (Foster et al, 2021). A chemically-induced impairment of TH homeostasis can induce adverse effects in rodent laboratory animals, such as the formation of thyroid tumors most likely resulting from sustained TSH stimulation or neurodevelopmental health implications.…”

Section: Introductionmentioning

confidence: 99%

“…A chemically-induced impairment of TH homeostasis can induce adverse effects in rodent laboratory animals, such as the formation of thyroid tumors most likely resulting from sustained TSH stimulation or neurodevelopmental health implications. Indirect (TSH-mediated) neoplastic changes of the thyroid gland in rodents are generally accepted to have little human relevance, acknowledging interspecies differences in the physiology of thyroid hormone homeostasis affecting the vulnerability to perturbation (Meek et al, 2003;Bartsch et al, 2018;Foster et al, 2021). But there are also safety concerns related to a decreased and potentially insufficient supply of TH, especially during pregnancy with direct health implications for the developing offspring (Noyes et al, 2019;O'Shaughnessy and Gilbert, 2020;Marty et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

A rodent thyroid-liver chip to capture thyroid toxicity on organ functional level

Karwelat

Kühnlenz

Steger‐Hartmann

et al. 2022

ALTEX

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Endocrine disruption by environmental chemicals continues to be a concern for human safety. The rat, a widely used model organism in toxicology, is very sensitive to chemical-induced thyroid perturbation, e.g. histopathological alterations in thyroid tissue. Species differences in the susceptibility to thyroid perturbation lead to uncertainty in human safety risk assessments. Hazard identification and characterization of chemically induced thyroid perturbation would therefore benefit from in vitro models addressing different mechanisms of action in a single functional assay, ideally across species. We here introduce a rat thyroid-liver chip that enables simultaneous identification of direct and indirect (liver-mediated) thyroid perturbation on organ-level functions in vitro. A second manuscript describes our work toward a human thyroid-liver chip (Kühnlenz et al., 2022). The presented microfluidic model consisting of primary rat thyroid follicles and liver 3D spheroids maintain a tissue-specific phenotype for up to 21 days. More precisely, the thyroid model exhibits a follicular architecture expressing basolateral and apical markers and secretes T4. Likewise, liver spheroids retain hepatocellular characteristics, e.g. a stable release of albumin and urea, the presence of bile canalicular networks, and the formation of T4-glucuronide. Experiments with reference chemicals demonstrated proficiency to detect direct and indirect mechanisms of thyroid perturbation through decreased thyroid hormone secretion and increased gT4 formation, respectively. Prospectively this rat thyroid-liver chip model, together with its human counterpart, may support a species-specific quantitative in vitro to in vivo extrapolation to improve a data-driven and evidence-based human safety risk assessment with significant contributions to the 3R principles. *

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A review of species differences in the control of, and response to, chemical-induced thyroid hormone perturbations leading to thyroid cancer

Cited by 29 publications

References 225 publications

Mechanisms by Which Inducers of Drug Metabolizing Enzymes Alter Thyroid Hormones in Rats

Mechanisms by Which Inducers of Drug Metabolizing Enzymes Alter Thyroid Hormones in Rats

A Collaborative Initiative to Establish Genomic Biomarkers for Assessing Tumorigenic Potential to Reduce Reliance on Conventional Rodent Carcinogenicity Studies

A rodent thyroid-liver chip to capture thyroid toxicity on organ functional level

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